The human inherited disorders of sphingolipid metabolism (Gaucher disease, Krabbe disease, Niemann-Pick disease, metachromatic leukodystrophy, etc.) are characterized, particularly in their infantile forms, by severe mental retardation, neurological degeneration, and various specific symptoms. Research on these disorders has been severely hampered by the lack of animals bearing the same genetic errors. We hope to induce model versions of the disorders by synthesizing and administering inhibitors of the sphingolipid hydrolases to young rats. The progressive changes in the brain and other organs will be followed by chemical assays, enzyme assays, isotope uptake measurements, and morphological examination. Other new compounds will be synthesized that will block the enzymes which synthesize sphingolipids. It is possible that they will alleviate the model disorders by slowing the rate of accumulation of the lipid whose hydrolysis is blocked. We hope also to synthesize substances which will stimulate the defective human enzymes; if sufficient stimulation can be attained, these may have therapeutic value. It is expected that use of the new compounds will clarify the role of the sphingolipids in normal and pathological human brain operation, as well as other functional roles of these lipids.